Syphilis continues to be a major health problem in the United States and in the developing world. In addition to serious individual health risks due to untreated infection, syphilis is a co-factor for acquisition and transmission of human immunodeficiency virus infection. Recently, a new gene family was discovered in Treponema pallidum. The proteins encoded by these genes have homology to the major sheath protein (msp) of a related spirochete, T. denticola. Their predicated structure contains conserved. Preliminary studies strong support this hypothesis, and demonstrate that this proteins are central to the pathogenesis of syphilis and to immunity to infection. This gene family and its encoded proteins are the focus of the studies proposed in this application. The broad objectives of this Program Project are the following: 1. To explore the mechanisms of persistence of T. pallidum in the infected host via antigenic variation or phase variation. 2. To understand the immune response during syphilis and to explore the influence of that immune response on the expression of antigens by T. pallidum. 3. To define the antigens that can confer protective immunity to syphilis infection. Each of the three projects contained in this application will address one or more of these objectives in complementary ways. This proposed program is an outgrowth of cooperative and synergistic research on syphilis that has been carried out in the University of Washington over the past decade. It integrates the expertise of molecular biologists, immunologists, and clinicians in the examination of exciting, newly identified genes and molecules of Treponema pallidum that hold promise for explaining a number of the unsolved mysteries of syphilis.